As we begin this brief review of the neurobiology of major depressive disorder (MDD), we face these fundamental questions:

• Will the provided information be clinically relevant?

• Can current scientific research provide us with a coherent, comprehensive, and relatively accurate description of the underlying neurobiology of MDD?

Major depression, bipolar disorder (BD),1 and generalized anxiety disorder (GAD)2 are all characterized by a significant genetic contribution to their etiopathogenesis. Heritability estimates for MDD have exceeded 70%3 in some studies, and BD may be even more genetically based, with estimates reaching the 80% to 90% range.4 Interestingly, MDD is more frequently reported in the families of bipolar patients than is BD itself; this finding suggests a partially shared diathesis and likely a “correlated liability,” if not an affiliation with the same continuum.5 Similarly, the genetic and clinical overlap between MDD and GAD is so extensive that some authors have gone so far as to suggest that they are dual manifestations of the same underlying pathophysiology.6

It is becoming increasingly clear that relationships between MDD, GAD, and BD run deeper than symptomatic similarities shared by these conditions. Although not always consistent, studies point to shared genetic underpinnings for these disorders, emphasizing genes involved in the regulation of monoaminergic and peptide transmission, inflammatory responses, diurnal rhythms, and neurotrophic signaling.4,7 All of these are important modulators of anxiety, mood, and stress responses. Furthermore, symptoms of anger, depression, and anxiety are strongly correlated with one another.8 Stress, in turn, is a major precipitant, perpetuant, and aggravating factor of all 3 conditions. However, one must temper any rampant “clumping” enthusiasm with the recognition that—as with similarities—differences between symptom presentations have also frequently been found. Simple links between genes and symptom–based disorders are complicated by a number of factors, including:

• The most common “vulnerability genes” for mood and anxiety disorders account for relatively little variance.

• A gene for 1 product may produce an array of behavioral outcomes, given that its product is typically ensconced in larger circuits that tend to demonstrate final common pathway–type phenomena.

• Symptom presentations in any given person are likely to result from intricate interactions between multiple genes and environmental factors.7,9

Examples of these types of interactions include epistasis (interactions between the genes) and epigenetic modulation (influences of life experience on gene expression).10 Acknowledging these important distinctions takes us a step closer to more effective personalized care.

It is no surprise that brain circuits involved in the regulation of mood, anxiety, and the stress response overlap to a significant degree with components of a “pain matrix” (areas mediating emotional and cognitive aspects of pain processing) as well as with structures involved in sleep regulation.11–13 From an evolutionary perspective, it is apparent that sleep deprivation, negative emotion, and physical pain all play key adaptive roles. All these apparently disparate phenomena provide a clear signal that current conditions are a threat to an organism’s survival.

Before we further elaborate on the roles and interactions between “danger, reward, and executive circuitries and pathways” in mood disorders, it is important to define these constructs more precisely. Reference to “circuitry and pathways” denotes discrete dynamic functional states of neural network rather than specific neuroanatomic entities. For example, depending on the pattern of “inputs,” nucleus accumbens, amygdala, hippocampus, anterior cingulate cortex [ACC], and paralimbic prefrontal cortex can be alternatively considered as components of either “reward/opportunity” or “danger/threat” pathways.14,15 Their cumulative interactions generate corresponding “outputs” or symptoms (much as one set of musical instruments can be used to produce a joyous or a mournful tune). Given the constant flow of internal and external information, there is a continuous flux of functional states, perpetuating the neural network’s adaptive and homeostatic roles.

In keeping with their shared role in alerting an organism to danger in the external or internal environment (ie, infection/tissue damage), peripheral and central “pathways” of anxiety, depression, and pain overlap significantly.16–18 They are all woven into the mammalian stress and immune response systems. While there are important differences in the sensory processing of anxiety, stress, and pain signals at the cortical and subcortical levels, (eg, dorsal column, thalamus, and primary and secondary somatosensory cortices [SI, and SII]), striking similarities are apparent in the involvement of limbic areas and paralimbic prefrontal cortex, amygdala, hippocampus, insula, ACC, ventromedial prefrontal cortex, as well as more “cognitive” and integrative brain areas, such as rostral ACC, dorsal ACC, dorsomedial prefrontal cortex, and dorsolateral prefrontal cortex.12 Imaging studies of persons experiencing depression, anxiety, spontaneous pain, social isolation, or sleep deprivation, bear more than little resemblance.